Overweight and obesity
Obesity is a disease especially widespread in prosperous, industrialized countries. Obesity can be defined as an excessive accumulation of fat in the body. Such excessive accumulation of fat can take place as a consequence of an energy intake which is greater than the energy expenditure, arising from either an excess of energy intake (i.e. a surplus of food) or a reduced energy expenditure.
For practical purposes, it is generally agreed that overweight is present if the body weight exceeds the "desirable weight", whereas obesity is present if the body weight is 20% or more above the "desirable weight" (1). Desirable weights for humans can be defined according to Metropolitan Height and Weight Tables (1) as the midpoint of the range of the medium-frame individuals.
Obesity can be classified as a mild (20-30% overweight), moderate (30-60% overweight) or a severe (.gtoreq.60% overweight) condition. Obesity is accompanied by a number of health hazards. It may impair both cardiac and pulmonary functions, perturb endocrine functions and cause emotional problems. Hypertension, impaired glucose tolerance and non-insulin dependant diabetes mellitus and hypercholesterolemia are more common conditions in overweight individuals than in individuals of normal weight. Obesity may therefore contribute to morbidity and mortality in individuals suffering from e.g. hypertension, stroke, diabetes mellitus type II, some types of cancer, gallbladder disease and ischaemic heart disease. Moderate and severe cases of obesity are known to increase mortality. Colonic and rectal cancer are diseases which frequently appear in obese men, and obese women often suffer from endometrium or gallbladder cancer. Furthermore, it is realized that an increase in overweight almost consequently leads to a rise in psychic and social problems.
Methods of treatment
The causes of obesity are complex and not fully understood. Obesity can be a result of life-style, i.e. of patterns of physical activity and food consumption, or a result of genetic propensity of the obese person. Genetic influences are generally considered to have an important role in determining human fatness and obesity. Furthermore, adverse reactions in the form of development of obesity can be seen after therapeutic treatment with various drugs.
The basic principle of treatment of obesity or overweight is to establish a negative energy balance. A negative energy balance can be accomplished using mainly three different methods of treatment or combinations thereof.
Firstly, an effective treatment is the reduction of energy intake, i.e. food intake. This is essentially possible only through a dietary treatment as malabsorption of food cannot be obtained safely either through medication or surgery. The dietary treatment must consist of a weight reducing diet as well as a maintaining diet. After a satisfactory weight loss, the energy supply must slowly be increased until the weight has stabilized on a supply of food which is nutrious and acceptable for the patient. The importance of a long-term diet is seen from the fact that only 10-20% of the patients are able to maintain their obtained reduced weight.
Secondly, increase in physical activity will lead to increased energy expenditure and consequently contribute to a negative energy balance. However, in order to obtain a significant weight loss, hours of daily physical activity is needed. Physical activity alone therefore plays a minor role in the treatment of obesity, although it is a very important supplement to other kinds of treatment. Also, physical activity can contribute to diminution of the decrease in energy expenditure which follows a dietary treatment comprising an energy restriction.
Thirdly, drugs can be used in the treatment of obesity, either alone or in combination with a dietary treatment and/or increased physical activity. The drugs used in the treatment of obesity can be appetite-reducing drugs and/or thermogenic drugs. Often, however, some overlap will be observed within the two categories. The appetite-reducing drugs exert their effect primarily by decreasing energy intake. The reduction in food consumption is a consequence of the drug action on the brain transmitter systems that are involved in the appetite regulation. The action of these drugs is supposed to be mediated through the hypothalamus at various sites. The action can be exerted through the adrenergic, the dopaminergic or the serotonergic pathway or a combination thereof. Whichever system is involved, the final result is a stimulation of the satiety center and eventually a simultaneous decrease in activity of the feeding center which results in a depressed appetite. Examples of known appetite-reducing agents are e.g. ephedrine, phenylpropanolamine, amphetamines and fenfluramine.
Thermogenic drugs in the treatment of obesity are now generally accepted to possess a potential therapeutic value, and in the recent years there has been a growing interest in the search for new thermogenic compounds. The interest is primarily related to the well accepted suggestion that obesity might be genetically determined. The genetic defect responsible for the possible development of obesity relates to a thermogenic defect (i.e. a defect in the metabolic system) of the obese person (2). Although the nature of the thermogenic defect is not fully clarified, there is a compelling evidence that points to a defective reactivity of the sympatoadrenal system (3). Dulloo & Miller (2) suggest that the thermogenic defect of the obese persons relates to a reduced release of norepinephrine rather than to an insensitivity to the neurotransmitter. Drugs which mimic the activity of the sympathetic nervous system and increase metabolic rate therefore offer considerable therapeutic potential for the treatment of obesity.
A thermogenic drug can be defined as a drug capable of raising metabolic rate, i.e. increasing the energy expenditure. Known thermogenic drugs are e.g. ephedrine, epinephrine, norepinephrine (4), isoproterenol, phenylpropanolamin and caffeine (5).
Studies concerning treatment of obesity in animals as well as in humans have been carried out with thermogenic drugs either alone or in combination. It has recently been shown that the major tissue of thermogenesis in rodents is the brown adipose tissue (BAT) (4). This is supported by the finding that resistance to obesity during voluntary overfeeding in rats and mice is due to an enhanced thermogenesis in BAT. It has been suggested that BAT is a determinant of energy expenditure in humans as well, and that defective thermogenesis in BAT contributes to human obesity. Human BAT receives sympathetic innervation, but the amounts of BAT are minute. It has been demonstrated that the thermogenic potential of human BAT is of minor importance compared to the total thermogenic response of the body (4). Resting skeletal muscle may contribute with at least 50% to the whole body thermogenesis induced by ephedrine (6), and skeletal muscle is probably a major determinant of resting metabolic rate as well as of the thermic effect of food in man (7). The major determinant of thermogenesis is thus quite different in man and rodents which makes a comparison between results from human and rodent studies meaningless. Thus, only results from human studies are reported in the following.
Dulloo & Miller (8) have recently shown that an over-the-counter tablet containing ephedrine and methylxanthines (22 mg ephedrine, 30 mg caffeine and 50 mg theophylline) (Do-Do pill, Ciba Geigy, UK) was twice as effective as ephedrine alone in increasing the fasting metabolic rate of both obese and lean human volunteers. As outlined in a review by Dulloo & Miller (2), it seems that the influence of methylxanthines effect of ephedrine but no detailed study seems to have been carried out in humans.
Cesarii et al. (9) have reported a randomized double-blind 4 months study in obese women. The women received either ephedrine alone (50 mg), ephedrine plus caffeine (50 mg+100 mg) or placebo without active drug(s), respectively, the drugs being administered orally. The study showed no significant difference in weight loss in the three treatment groups, indicating no interaction between ephedrine and caffeine.
The "Elsinore tablet" (10) consisting of ephedrine 20 mg, caffeine 55 mg and bisacodyl 1 mg was initially used against asthma but was observed to cause weight loss. This composition has been compared with ephedrine 20 mg (2+2+1 tablet per day) in a double-blind clinical trial on 64 obese patients (41). After 18 weeks, the average weight loss was 7.9 kg and 9.4 kg after administration of the ephedrine tablets and the "Elsinore tablets", respectively. However, the difference was not statistically significant (P&gt;0.10).
Oral compositions with a combination of phenylpropanolamine hydrochloride and caffeine have been described in literature (11). Caffeine has probably been added to these compositions in order to allay fatigue (12) as caffeine has stimulating properties.
Various other combinations of ephedrine or pseudoephedrine and methylxanthines have emerged as over-the-counter pharmaceutical compositions for treatment of bronchial cough, wheezing, breathlessness and to clear the chest. In accordance with these therapeutic indications for use of such combinations, the potential use of such over-the-counter products as thermogenic compositions have not been reported according to our knowledge, except in the case of the Do-Do pill as referred to above in the study of Dulloo & Miller (8).
Carcass quality in domestic animals
Improvement of carcass quality, i.e. decrease in the fat tissue mass/lean body mass ratio, in meat animals is a goal in livestock science, because excess fat production are sources of inefficiency in the livestock and meat processing industry. Furthermore, excessive intake of dietary lipid by humans has been linked to an increased occurrence of coronary heart diseases in the human population.
Carcass composition of meat animals can be changed by feeding strategy using entire males or by killing animals at lower proportion of mature weight and through selection programs.
In addition, anabolic steroids have been extensively used in cattle to stimulate body growth and protein deposition. However, the anabolic steroids have recently been banned in the EEC countries which has contributed to an increased attention to new classes of compounds, such as .beta..sub.2 -adrenergic agonists (clenbuterol, cimaterol, ractopramine and salbutamol (42-45)) and growth hormone.